During medical diagnosis using X-ray a large part of human tissues are not visible because of the low density and thickness difference of these tissues. It is therefore necessary to introduce a material which changes their absorptivity of X-rays in order to acquire a clearer image to confirm the veracity of the diagnosis. This material is called a contrast agent.
Elements with higher atomic number have increased photoelectric effects with X-rays. The range of the spectrum of the absorption frequency of X-rays by an element is largely dependent on its arrangement of the extra nuclear electrons. The frequency of the X-ray utilized for medical diagnosis is attuned to the X-ray absorption spectrum of the barium atom and the iodine atom. Therefore, these two elements create high density shadows during X-ray imaging.
Iodinated contrast agents are a series of compounds which are widely used in X-ray imaging diagnosis techniques. Second generation non-ionic contrast agents are currently and mainly utilized in clinical practice. These include, Iopamidol, Iohexol, Iopromide, Iomeprol, Iopentol and Ioversol. More recently developed dimer type non-ionic contrast agents have lower osmotic pressure and lower side effects. Two examples for this type of contrast agent are Iotrolan and Iodixanol.
The wide application of iodinated contrast agents results in their huge demand. This has prompted pharmaceutical enterprises all over the world to carry out a series of studies on the development and improvement of the synthetic process of this type of contrast agent.
It is obvious that the molecular backbone of these types of contrast agents share a tri-iodinated aromatic nucleus as shown in follow drawing:

This structure illustrates that the ratio of the number of iodine atoms per molecule of the contrast agent is 3/1 for a monomeric agent or 6/1 for a dimer, which provides enhanced contrast effect. It is therefore obvious that 3,5-disubstituted-2,4,6-triiodo aromatic amines are key intermediates for the synthesis of this type of iodinated contrast agent in common synthetic routes.
The abundance of iodine in the nature is low. This means that iodine and its related compounds which are used as iodinating reagents are relatively expensive. Summing up the above, if an advanced process which is appropriate for the synthetic step shown in the following transformation could achieve high yield, reasonable consumption of the iodination reagent and a reasonable cycle time, it would have great significance on the industrial production of 3,5-disubstituted-2,4,6-triiodoaniline intermediates and subsequently the contrast agents themselves.

Development of the new iodination process would start at selecting an appropriate iodinating reagent. A system wherein the reagent is equivalent to the iodine cation (I+) is required for this reaction and follows the well-known aromatic electrophilic substitution mechanism. A traditional method usually described in references and patents is using IX (iodine cation (I+) mono-halide) as the iodination reagent. And there is no doubt that ICl is the most practical choice of this type of iodination reagent on an industrial scale.
Generally this type of process uses a solution of ICl in concentrated HCl as the iodination reagent to react with the aromatic nucleus of the substrates at about 90° C. The process disclosed in U.S. Pat. No. 5,013,865 (Mallinckrodt, Inc.) is a typical example. ICl reacts with water and is converted to hypoiodous acid and hydrogen chloride, but since this type of iodination reaction is usually carried out in aqueous media an alkali metal halide salts such as NaCl or KCl is commonly required to stabilize ICl. Hence, this means that analogous iodinating reagents such as NaICl2 or KICl2.
U.S. Pat. No. 5,013,865 and U.S. Pat. No. 6,274,762 (Nycomed Imaging AS) describe the general method to prepare NaICl2 or KICl2:I2+Cl2+2NaCl/KCl(aq.)=2NaICl2/KICl2(aq.)
In patent application US 20110020238 (GE HEALTHCARE AS) discloses a process of adding salts such as NaCl or KCl to the aqueous solution of ICl to stabilize it for storage. The method of preparing ICl described in this patent application is shown in the following equation:3I2+NaClO3+6HCl=6ICl+NaCl+3H2O
The basis of this method is the use of an oxidant agent to convert iodine to ICl in the present of Cl−. ClO3− will be partly reduced to Cl2 as shown in the following equation:6I2+11NaClO3+3H2O=6KH(IO3)2+5KCl+3Cl2 
These processes, utilizing ICl, share a common feature in that ICl needs to be pre-prepared prior to reaction. This means that a second corrosion resistant vessel is required in addition to the reaction vessel for the iodination step in order to produce and store ICl. This represents a disadvantage in terms of the cost and the operational arrangement sequence. In addition, the alkali metal halide added to stabilize the iodinating reagent increases the overall content of salt in the product and makes the workup after of the iodination reaction more difficult. The process disclosed in the patent application US 20110021834 (GE HEALTHCARE AS) also does not avoid these drawbacks.
Yet another negative aspect of the ICl type iodination reagents can be gleaned from its reaction mechanism:

The generation of HCl will lead to a rapid increase of the acidity of the reaction system. This is a serious challenge to the corrosion resistance of the equipment. Furthermore, under high acidity a reaction which generates acid will be going to complete conversion only with difficulty.
Hence it is necessary to use a large excess of the iodination reagent to maintain a reasonable percentage conversion. In addition more diiodinated products can be expected when the conversion is slow thus affecting the quality of the product.

But the worst drawback of ICl type iodinating reagents is that the reagent itself contains a larger amount of chlorine atoms/ions. Chlorine itself can bond to the aromatic nucleus at the high temperature of the process resulting in the introduction of impurities which are chlorinated on the aromatic nucleus. These impurities are subsequently very difficult to be removed in downstream processing. In particular, in either of the two methods to prepare ICl type iodinating reagent system described a small quantity of highly reactive Cl2 will be formed, resulting in formation of chlorinated impurities in the product. The most typical of these chlorinated impurities is the mono-chloro impurity shown as follows:

It is therefore necessary to develop new chlorine-free iodinating reagent systems in order to eliminate the adverse effects caused by chlorine in the system. As described above any reagent system which produces a substance which is equivalent to the iodine cation (I+) may be suitably used for poly-iodination of aromatic substrates. Hence, the primary task of developing new iodinating reagent system is designing a system which carries out these types of reactions.
Iodine, being a halogen, requires a strong oxidation system to reach the oxidation number of +1. Besides by preparing iodine mono halides, electrochemistry methods can also achieve this objective. Patent application US 20100331567 (Bracco Research USA Inc.) has disclosed a method to produce triiodinated aromatic compounds by electrochemistry. The essence of this method is to remove an electron from the iodine atom at the electrode in order to form I− in the reaction system. The positively charged iodine then attacks the substrate to obtain the iodination product.

This electrochemical method needs to be developed significantly to surmount many problems before becoming practical at an industrial scale preparation level as the design of industrial scale electrolytic cells is not as easy as the design of a classical stirred tank reaction vessel. In addition the method itself introduces many byproducts into to the product. Notwithstanding, this method does provide guidance for the development of new a chlorine-free iodinating reagent system.
Patent application WO 2010121904 (Bracco Imaging Spa) discloses a process for the preparation of 5-amino-2,4,6-triiodo-isophthalic acid by direct iodination of 5-aminoisophthalic acid using oxidant activated iodine. The preferred oxidant of this process is HIO3, as shown in the following equation:

This patent application considers that the mechanism of this reaction involves the iodine cation (I+) as the effective iodinating species wherein at least a portion of which is first generated via molecular iodine (I2), whilst the unreactive iodide ion acts as the anionic counter-ion (I−). In this way the side product, iodide, is conveniently oxidized by the oxidizing agent back to molecular iodine, or even to iodine cations with a higher oxidation state. Thus all of the iodine is made available for the iodination of the aromatic ring. Thus, the objective of direct iodination of the substrate to obtain the required product using activated iodine is achieved.
Both the method of electrochemistry and the method of activating molecular iodine by oxidation share a fundamental similarity in that the I+ iodinating species is generated in situ from molecular iodine. These two methods could be consider as the same type of new iodination reagent systems for the preparation of 3,5-disubstituted-2,4,6-triiodo aromatic amines. Compared with the ICl type iodination reagent system, the difference is in the existence of the activated iodine at the oxidation number of +1 meaning they are not the same. The method which activating iodine by oxidizing conveniently avoids the introducing of chlorine into the reaction system, thereby basically avoiding the formation of mono-chloro impurities in the product as mentioned above.
All types of iodination reagent systems will form free iodine in the crude product. From an industrial perspective, iodine is relative the most expensive of all of the reactants. However, the above mentioned patent documents rarely discuss the problem of recovering and reusing the excess iodine. In most of the process disclosed in these patent documents, residual iodine was removed by directly adding a reducing agent such as sodium sulfite. This is a drawback when considering the process costs.
In summary, in order to improve the extensively used process utilizing ICl type iodination reagents, two key points should be taken into consideration: controlling the content of partly iodinated species such as diiodinated intermediates in the product; avoiding the formation of chlorinated impurities, such as mono-chloro impurity, which are hard to remove, from the product. In addition, improvement of the yield of the iodination and optimization of the utilization of iodine are also of significant importance.